Hepatitis delta virus (HDV) is an infectious agent dependent upon hepatitis B virus (HBV) for the formation of viral particles. The HDV genome is a small single-stranded RNA of approximately 1700 nucleotides in length that is circular in conformation. The genome RNA is capable of folding using about 74% base pairing to form an unbranched rod-like structure. Replication of the HDV genome occurs through a symmetrical rolling-circle mechanism that involves RNA intermediates, and results in the accumulation of new genomes and complementary RNA species known as antigenomes. In a classic HDV:HBV infection, up to 300,000 copies of genome and 100,000 copies of antigenome accumulate per infected cell during HDV genome replication. It is believed that the genomic and antigenomic RNA circles act as templates for the generation of the multimeric strands of both polarities, which are greater than the 1700-nucleotide unit length. These are processed to unit length RNAs due to the presence of a site-specific ribozyme sequence in both the genome and antigenome. After ribozyme cleavage, the unit-length RNAs are ligated to form new circular RNA species. Since HDV does not encode its own replicase and can replicate autonomously in its host, one or more host RNA polymerases are redirected for its replication (Taylor and Pelchat, Future Microbiol 5:393-402, 2010).
A third HDV RNA species approximately 900 nucleotides in length and of antigenomic polarity is also produced at approximately 500 copies per infected cell in the classic HDV:HBV infection. The open reading frame of this RNA encodes a protein that is 195 amino acids in length and is referred to as the small delta antigen (S-HDAg). During replication, an adenosine deaminase that acts on dsRNA converts an adenosine in the termination codon of S-HDAg to an inosine. This amino acid conversion leads to the generation of an mRNA where the termination codon encodes tryptophan, resulting in the production of a second viral protein species that is 19 amino acids longer at the C-terminus, referred to as the large delta antigen (L-HDAg) (Taylor and Pelchat, Future Microbiol 5:393-402, 2010).